1,4-Dioxane-2,5-dione, 3,6-dimethyl-, (3R,6R)-

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

An in vitro study of the effects of formulation variables and product structure on percutaneous absorption of lactic acid

Author:

Sah, A; Mukherjee, S; Wickett, RR

Year:

1998

Bibliographic source:

J. Cosmet. Sci. 49, 257-273

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

In vitro dermal absorption study.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

L-(+)-lactic acid

EC Number:

201-196-2

EC Name:

L-(+)-lactic acid

Cas Number:

79-33-4

Molecular formula:

C3H6O3

IUPAC Name:

(2S)-2-hydroxypropanoic acid

Specific details on test material used for the study:

L+[14C(u)] lactic acid, specific activity 150 mCi/mmol, was obtained from American Radiolabelled Chemicals Inc. The following chemicals were used in formulation of the emulsions: a hydrophilic surfactant (Synperonic PE/F127, a block copolymer of ethylene oxide and propylene oxide; Icr Surfactants, Wilmington, DE); a lipophilic surfactant (Hypermer A60, a modified polyester; ICI Surfactants); lactic acid (USP grade; Purac); paraffin oil (Penreco); and propylene glycol (Fischer Chemical), The scintillation cocktails used were Ecolume™ (ICN), Scintiverse7 Scintanalyzer™ (Fischer Chemicals), and NCS-II- Tissue solubilizer (Amersham Canada Limited).

Radiolabelling:

yes

Test animals

Species:

other: Pig skin

Administration / exposure

Type of coverage:

occlusive

Vehicle:

other: emulsion

Duration of exposure:

6 hours

Doses:

2 µL and 75 µL

Results and discussion

Signs and symptoms of toxicity:

not examined

Dermal irritation:

not examined

Absorption in different matrices:

Absorption in stratum corneum, epidermis, dermis, and receptor fluid was determined

Percutaneous absorption

Percutaneous absorption 1

Time point:

6 h

Dose:

2 µL

Parameter:

percentage

Absorption:

ca. 16 %

Remarks on result:

other:

Remarks:

Worst case conditions: low dose, o/w emulsion; Stratum Corneum

Percutaneous absorption 2

Time point:

6 h

Dose:

2 µL

Parameter:

percentage

Absorption:

ca. 2 %

Remarks on result:

other:

Remarks:

Worst case conditions: low dose, o/w emulsion; Epidermis

Percutaneous absorption 3

Time point:

6 h

Dose:

2 µL

Parameter:

percentage

Absorption:

ca. 4 %

Remarks on result:

other: 6 h

Remarks:

Worst case conditions: low dose, o/w emulsion; Dermis

Percutaneous absorption 4

Time point:

6 h

Dose:

2 µL

Parameter:

percentage

Absorption:

ca. 0.5 %

Remarks on result:

other: 6 h

Remarks:

Worst case conditions: low dose, w/o emulsion; Receptor fluid

Applicant's summary and conclusion

Conclusions:

Skin absorption of lactic acid can be substantial, with up to 25% being present in skin after prolonged exposure to low doses of high concentration formulations. This is expected and often wanted as lactic acid is a well known humectant (skin moisturizer) in cosmetic applications. The dermal uptake of lactic acid leading to systemic exposure is much lower; even under worst case conditions, the transdermal uptake is less than 1% of the applied dose.

Executive summary:

The efficacy of lactic acid-containing products is linked to their ability to deliver it to specific skin strata. The penetration of L(+)- lactic acid to different skin layers of porcine skin from various emulsions was measured in vitro using flow-through diffusion cells. The effects of pH, propylene glycol, product structure, and mode of application on percutaneous absorption of lactic acid were investigated. The absorption of lactic acid from oil-in-water (o/w) emulsions was measured at pH 3.8 and 7.0. The effect of propylene glycol (5 %) as a penetration enhancer for lactic acid was also investigated from an o/w emulsion. The emulsion was applied either as a finite-dose 2-µl topical film or as a 75-µL "infinite" dose occluded patch on a 0.64 cm² skin disc. A key finding was that the effects of changes in product compositions such as vehicle pH and propylene glycol on percutaneous absorption of lactic acid depended on the application mode. Increasing the aqueous phase acidity in an oil-in-water emulsion enhanced lactic acid delivery in the finite dose but not in the infinite-dose application. Finite-dose films were significantly more efficient than infinite dose for lactic acid delivery to tissue compartments. The penetration enhancer propylene glycol was more efficacious at the infinite-dose application. However, it also significantly enhanced lactic acid delivery to viable epidermis in the finite-dose application. Finally, the effect of emulsion phase structure on lactic acid uptake was investigated by comparing delivery from oil-in-water (o/w), water-in-oil (w/o), and water-in-oil-in water (w/o/w) multiple emulsions with identical compositions. The total tissue delivery of lactic acid from the three emulsions was in the order of o/w > w/o/w > w/o.